One of the major concerns among doctors and patients with testosterone therapy is its allegedly negative effect on the prostate.1 However, according to the current ISA, ISSAM, EAU, EAA, ASA clinical guidelines, there is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia.2 The guidelines also state that there is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer.2

Despite this, many men are being denied testosterone therapy because of undue fears that it would cause harm to the prostate. In this editorial we summarize the results from a study that investigated incidence of prostate cancer with testosterone therapy for up to 17 years.3

Key Points

In the combined study population, there were 11 cases of prostate cancer, translating into a proportion of 1.08%.3

This prostate cancer incidence (1.08%) is much lower than that reported in the general population of men who are not on testosterone therapy:

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality reported a prostate cancer incidence of 7.35% among 38,345 US men aged 55-74 years who were followed for 7 years.4

The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a prostate cancer incidence of 9.6% among 72,891 men aged 50-74 years who were followed for 11 years.5

This study shows that testosterone treatment with Nebido® for up to 17 years does not increase the risk of prostate cancer3, which supports previously presented new insights on the testosterone - prostate relationship, and the saturation limit of androgen-dependent prostate growth.6,7

Testosterone therapy has no clinically significant adverse impact on prostate cancer incidence among men regardless of administration method.8

What is known

Medical students and doctors have been taught since the 1940s that high testosterone levels supposedly promote the development of prostate cancer, that low testosterone is protective, and that the administration of testosterone to a man with subclinical or existing prostate cancer would speed up its progression.9 This fear is also the most common reason for doctors' reluctance to prescribe testosterone replacement therapy, even in hypogonadal men1,10.

What this study adds

In the study by Haider et al, 1,023 hypogonadal men (from three independent registry studies) with total testosterone ≤12.1 nmol/L (350 ng/dL) and symptoms of hypogonadism received testosterone therapy with testosterone undecanoate (1000 mg) (Nebido®) in intervals of 12 weeks, following an initial interval of 6 weeks, for up to 17 years. Age at baseline was 41-58 years. At baseline, majority of patients exhibited a host of comorbidities, especially obesity, pre-diabetes and type 2 diabetes, erectile dysfunction, BPH/LUTS and dyslipidemia. This is in line with the well documented high prevalence of hypogonadism in men with these medical conditions.

The notable result in this study is that the incidence of prostate cancer among men who had been treated with testosterone therapy using Nebido® for up to 17 years was lower than the incidence of prostate cancer that is seen in the general population of men who are not treated with testosterone therapy; only 1.08%3 compared to 7.35 to 9.6%.4,5 In order to precisely calculate the incidence of prostate cancer in relationship to the exposure time to testosterone therapy, the incidence per 10,000 patient-years was calculated. This allows for an at least rough comparison of studies of different size and duration. The incidence per 10,000 patient years was 39.4, 54.4 and 0 for the three different registry studies described in Dr Haider’s paper3, compared to 116 in the PLCO4 and 96.6 in the ERSPC5 studies. In addition, all cancers were low-grade, simply because they were detected early as patients on testosterone therapy are very well monitored, as advised by all major clinical practice guidelines (ISA, ISSAM, EAU, EAA, ASA and US Endocrine Society).11,12

The results from this study are consistent with findings from another study that investigated prostate outcomes after treatment with testosterone patches for 6 years, which also documented that there was no signal for an increased prostate cancer risk with testosterone therapy.13

This long-term study with Nebido® clearly demonstrates that testosterone therapy does not increase risk for development of prostate cancer. It also supports previous observations showing no association between endogenous testosterone levels and prostate cancer14,15, and meta-analyses which conclude that there is no clinically significant adverse impact on prostate cancer incidence among men on testosterone therapy, regardless of the administration method.8,16

There is also no correlation between testosterone therapy and increased aggressiveness of prostate cancer at diagnosis.17 A systematic review of testosterone therapy and potential prostate cancer risk among men with and without a history of prostate cancer found that no study demonstrated that testosterone therapy for hypogonadism increased prostate cancer risk or worsened Gleason score of detected cancer in treated vs. untreated men.18 Therefore, withholding testosterone therapy in hypogonadal men, also in men who have been successfully treated for prostate cancer, is not justified.19

Despite the widespread belief that testosterone therapy is contraindicated in hypogonadal men with known or suspected prostate cancer20, there is no convincing evidence that the normalization of testosterone levels would increase risk for progression of prostate cancer.6,7 In view of the current available evidence, clinicians are compelled to consider these new data and abandon the old-school indoctrinated line of thought.7

According to Dr. Morgentaler, a leading clinician and researcher specializing in testosterone therapy and prostate safety, the negative view of testosterone with regard to prostate cancer should be recognized for what it is - guilt by association.21 Dr. Morgentaler also urges clinicians to turn conventional wisdom upside-down by correctly stating: "Finally, after 7 decades of circumstantial evidence pointing us in the wrong direction, perhaps it is time to consider the once unthinkable: a testosterone therapy trial of sufficient size and duration to determine whether normalization of serum testosterone in older men may reduce the risk of prostate cancer, particularly high-risk prostate cancer."22